Project Summary: Most scientific understanding of epigenetic biology is in the field of development and cancer. In my early career period, I have been investigating various pathways of pro-inflammatory signaling in the retina and have recently discovered a powerful ability for biochemical modification of histones, a protein that complexes with DNA to form the nucleosome, to regulate the expression of specific inflammatory factors found in AMD. The striking changes in pro-inflammatory gene signatures that can be induced by inhibiting deacetylation of histones suggest that this pathway may be involved in the pathogenesis of AMD. Preliminary data demonstrated decreased expression of critical enzymes involved in these pathways in advanced dry AMD eyes and in experimental models of oxidative stress. Inhibition of histone deacetylation resulted in significant cytotoxic effects on the retinal pigment epithelium. In this project, I plan to rigorously dissect the role of histone deacetylase expression and function in the pathogenesis of dry AMD and RPE cell death. These studies will employ advanced techniques in molecular biology including assays to map genome-wide changes in transcription in AMD and to recapitulate dysregulation of these important biological pathways in cellular and animal models with genetic engineering. The proposed work will directly address a fundamental lack of knowledge on the role of histone deacetylases in the regulation of retinal inflammation and cell death making the work underway critically important in our search for effective targeted therapeutics for dry AMD.